domingo, março 12, 2006

Aprovação de medicamentos na Europa

Europe's jungle of drug regulators

By James Kanter International Herald Tribune


Barbara Clark discovered she had early-stage breast cancer in February, had the tumor removed in March and started chemotherapy in April. Then Clark, a British nurse, opened a new front in June in her battle to get well - against the government.

Clark had read about Herceptin, a treatment for advanced breast cancer that new research showed might help at an early stage. But her doctor told her that the health authorities would not pay the annual bill, which runs to £30,000, or more than $50,000: The drug maker, Roche, was not even going to apply for approval until January.

After that, it would take months to get even fast-track approval at the European Medicines Agency, and then several more weeks of review at the National Institute of Clinical Excellence, a British body that advises the government on the effectiveness of approved drugs.

Unwilling to wait, Clarke waged a media campaign that eventually forced authorities to give her a subsidized prescription on "compassionate" grounds.

"I don't have a greater right to life than anyone else," said Clark, 49, who lives in Somerset, England. But, she added, "I didn't want to be among the last generation to die."

Many other anxious cancer patients are still waiting for Herceptin to be approved for early-stage breast cancer treatment. Only then will they be able to use it and obtain reimbursement from their health care provider - which in Europe is often the government.

To these people, at least, the affair underscores their argument that cumbersome regulatory practices, far from ensuring safety, actually put lives at risk.

"Women do not have time to wait for bureaucratic red tape, to wait for all the levels of approval that we now face," said Dorothy Griffiths, a member of Fighting for Herceptin, a pressure group.

But then The Lancet, the British medical journal, raised questions last week about Herceptin's effectiveness for early-stage breast cancer, noting that some women in studies had had heart problems that demanded further investigation.

With that, Herceptin became a clear example of the complexities and flaws in Europe's system for approving and distributing drugs. Getting a new medicine from the laboratory to the pharmacy shelf is a labyrinthine process.

Regulators are trying to streamline it, but in the meantime, a web of budgets, politics and restrictions on marketing sometimes conspires to prevent new medicines from reaching medicine cabinets as quickly as patients and industry would like, or at a price governments or individuals can afford.

Peter Sutherland, who has served as director general of the World Trade Organization and as the EU commissioner for competition policy, once called the splintered regulation of pharmaceuticals "the single most spectacular failure of the single market" in Europe.

Many European governments made universal health care essentially free after World War II. But there is a flip side. When funds run low - often as a result of pressure to reduce taxes - drugs become harder to get. Many of the delays creep in because European governments, now some of the largest health insurers on the planet, are reluctant to add expensive new drugs like Herceptin to their reimbursement rosters unless they are proved to be more beneficial than similar drugs already available.

The patchwork of public health care systems across Europe - ranging from big, rich countries like Germany to poor, smaller ones like Bulgaria - means the availability of drugs is often as much about the health of national budgets as about the need for safe and effective treatment.

Once a medicine is approved, the cost to patients - which is negotiated separately in each country - can be all over the map, depending on whether a government can afford reimbursement.

Meanwhile, rules that bar drug advertising in Europe also encourage pharmaceutical companies to generate buzz about medicines and to quell competition from generics and importers, which offer patients cheaper alternatives.

The first step in the long path from the lab to the pharmacy - determining whether a drug can be used for treatment - is fraught with complications.

Unlike the one-stop system in the United States, where the Food and Drug Administration has the sole power to approve or reject a medicine, drug makers seeking approvals in Europe may go through a pan-European checkpoint or through any of several national ones.

Depending on what the drug is, pharmaceutical companies may need to get approval from the European Union, through its European Medicines Agency, or they can knock on the doors of individual governments, with whom many companies have nurtured close contacts.

New rules could speed the ability to satisfy demand for access to next-generation drugs like Herceptin. As of next Sunday, drug makers will be obliged to seek EU-wide approval from the European Medicines Agency for all new medicines for major diseases, including AIDS, cancer, diabetes and neurodegenerative disorders, rather than seek direct government approval.

Antibiotics and heart drugs are among the few treatments that a national authority, like the medicines and health care products regulatory agency in Britain, will still be allowed to approve first.

But as governments seek to rein in spending on new drugs, they have added yet another layer to the approval system. In Britain, for example, the National Institute of Clinical Excellence judges whether medicines approved by safety regulators are valuable enough to be subsidized by the government.

For years, European governments had the sole power to approve medicines for their national markets.

In the early 1990s, as efforts to build a single European market gained a head of steam, the European Union won a mandate to establish an agency in London to centralize approvals for the EU market. The European Medicines Agency became a largely voluntary alternative for drug companies that would otherwise go to national governments for approval. The EU passed rules giving drug companies incentives to go to its agency instead.

Yet echoes of the old system remained. At the time of the European Medicines Agency's creation, drug makers were also given a second option for obtaining EU-wide approval that proved more popular. They could go to one member state first, without risk of intervention from any other countries, and later ask other countries to recognize the approval across the EU.

Companies rushed to countries where they had good relations with individual regulators. Germany, France, Britain and the Netherlands were popular choices.

In cases where countries did dispute approvals, the European Medicines Agency would arbitrate and in most cases force an approval. In the United States, by contrast, a drug maker may apply for approval only at the Food and Drug Administration, and its decision applies across the entire country.

Yet even when the European Medicines Agency does review a drug, part of the approval process is farmed out to member state agencies - usually two per drug - because national governments wanted to remain involved and because they had set up the EU agency with only a small core staff. Even so, critics say, this system created an environment that wound up favoring drug companies.

According to Silvio Garratini, who resigned 18 months ago as the Italian representative to the European Medicines Agency, it allowed companies to select one of the two member states that would be involved in reviewing their applications. It also allowed companies to withdraw applications in secret to avoid jeopardizing chances of approval elsewhere, if it looked like things were going badly, he said.

The agency's day-to-day operation is overseen by European Commission officials responsible for industrial policy, rather than health matters, said Garratini, who now heads the Mario Negri Institute for Pharmacological Research in Milan.

"Drugs," Garratini said, are "more important as goods for sale than as tools to protect the health of patients."

The agency said it would curb the practices criticized by Garratini, and its officials see the changes coming this month as an important step toward meeting patient demands more quickly and becoming more like the century-old Food and Drug Administration.

Martin Harvey Allchurch, spokesman for the European Medicines Agency, said the new emphasis on speedier, centralized approvals should help drug companies do business in the European Union by reducing paperwork and the scope for disagreement about safety.

Yet even as the agency gains powers for fast-track approvals, governments are scrambling to slow things down. Their main concern is to avoid significant new health care costs that could skyrocket as patients like Clark turn up the pressure to be reimbursed for expensive, high-profile new medicines.

This year, the German government set special criteria to determine whether a new drug is eligible for generous reimbursement terms. It began forcing drug makers to show that new medicines - including those already approved by the European Medicines Agency - represent a "significant therapeutic improvement" over similar ones already on the market. If a drug maker fails this test, the new medicine can be priced the same as cheaper medicines produced generically after patents expired.

When only two patented drugs had passed the test by February - one from Bayer of Germany and another from SanofiAventis of France - there was an outcry from the United States on behalf of its drug makers who failed to get patented drugs approved for reimbursement in Germany, said Neena Moorjani, spokeswoman for the Office of the U.S. Trade Representative.

The office sharply criticized Germany in its 2005 watch list, which serves as an early warning to countries suspected of undermining the value of U.S. brands and products.

But what some patient groups and the pharmaceutical industry fear most is that EU governments could one day require the European Medicines Agency itself to examine drugs in terms of their economic value, not just for quality, safety and efficacy.

Jeremy Smith of Health Action International, an Amsterdam-based pressure group partly financed by European governments, argues that therapeutic advance should be a condition of approval.

"Why, otherwise, should these companies be entitled to a vast financial reward?" asked Smith, who criticized the pharmaceutical industry for flooding the market with "me too" drugs for conditions like heartburn and high cholesterol that can generate high profits.

Many doctors agree that tests of value for money are necessary to maintain enough resources to offer nearly free universal health care. Any budget crunch, these doctors say, is likely to get worse as next-generation treatments become available, including those to help people lose weight, stop smoking or have better sex lives.

"There is a need to fast-track certain medications, but we also need to evaluate the evidence around a treatment to see how it squares up to other medicines already available," said Dr. Jim Kennedy, a general practitioner near London who heads the prescribing committee at the Royal College of General Practitioners, a 24,000-member association based in London. "Sooner or later in any system, you only have a finite amount to spend on health care."

At the European Medicines Agency, Harvey Allchurch sees this coming - one day.
"There is the tiniest possibility we will be tasked to look at therapeutic value," he said. "But that is way down the line."

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